MAPKAP-K2 (mitogen-activated protein kinase activated protein kinase 2) is a serine/threonine kinase and operates in immediate downstream of p38 kinase in stress-induced MAPK pathway (FIG. 1).
This p38 kinase pathway is activated by various stress-related extracellular stimuli such as heat, ultraviolet ray, bacterial lipopolysaccharide or inflammatory cytokines. The activation of this pathway causes phosphorylation of transcription and initiation factors and affects cell division, apoptosis, cell differentiation, inflammatory response and infiltration of cancer cells (Martin-Blanco, Bioessays 22, 637-645).
p38 Kinase itself activates many protein kinases other than MAPKAP kinase, for example, Mnkl/2, PRAK and MSK1 (FIG. 1). This pathway is particularly important for discovery of novel anti-inflammatory drugs. A selective p38 kinase inhibitor is effective for suppressing inflammatory cytokines in both cell based model and animal model of chronic inflammation (Lee et al., Immunopharmacology 47,185-201 (2000)). However, a p38 kinase-knockout mouse is embryonic lethal. Moreover, it has been proved that cells derived from such an embryo exhibit a lot of anomaly in fundamental cellular responses. As another strategy for developing anti-inflammatory drugs, there can be mentioned a drug inhibiting this pathway in the level of MAPKAP-K2. In an unstimulated cell, MAPKAP-K2 exists in the nucleus, and it is transferred to cytosol when the cell is stimulated. It is known that this kinase phosphorylates many nuclear transcription factors and cytosolic proteins such as heat-shock protein involved in cell protection and 5-lipoxygenase involved in bioprotection and inflammation (Stokoe et al., FEBS Lett. 313, 307-313 (1992); Werz et al., Proc. Natl. Acad. Sci. USA 97, 5261-5266 (2000)); Heindenreich et al., J. Biol. Chem. 274, 14434-14443 (1999)); Tan et al., EMBO J. 15, 4629-4642 (1996)); Neufeld, J. Biol. Chem. 275, 20239-20242 (2000)). All of these substrates contain a unique amino acid motif (XX-Hyd-XRXXSXX where Hyd represents a bulky hydrophobic residue) which is required for effective phosphorylation by MAPKAP-K2 (Stokoe et al., Biochem. J. 296, 843-849 (1993)).
MAPKAP-K2 is the only substrate of p38 kinase whose special function is currently identified. The special rolls of MAPKAP-K2 in mediation of inflammatory response are remarkably demonstrated in a phenotype of MAPKAP-K2 knockout mouse (MAPKAP-K2−/−) (Kotlyarov et al., Nature Cell Biol. 1, 94-97 (1999)). This mouse is not lethal and normal except for particularly reduced inflammatory response. Recently, it has been proved that lack of MAPKAP-K2 causes particular protection of neurons from ischemic brain injury (Wang et al., J. Biol. Chem. 277, 43968-43972 (2002)). It is considered that MAPKAP-K2 regulates translation and/or stabilization of mRNA of important inflammatory cytokines. This is likely because MAPKAP-K2 phosphorylates proteins which bind to AU-rich elements found in untranslated regions of these cytokines. Identification of these proteins is now under investigation.
Furthermore, it is reported that MAPKAP-K2 has activity of repairing anomaly in DNA induced by ultraviolet ray (Isaac A. Manke et al., Molecular Cell 17, 37-48 (2005)). Inhibition of MAPKAP-K2 activity may disable repairing damaged DNA and cause death in some types of cancer cell.
From the above, MAPKAP-K2 inhibitors are effective for neurodegenerative/neurological disorders (including dementia), sepsis, autoimmune diseases, destructive osteopathy, inflammatory bowel disease, psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma and/or chronic obstructive pulmonary disease (COPD).
As MAPKAP-K2 inhibitors there have been disclosed in WO2004/054504, WO2004/054505, WO2004/055015, WO2004/055019, WO2004/058176, WO2004/058762, WO2004/099127, WO2005/009370, WO2005/007092, WO2004/076458 and WO2004/081013, but these compounds are different in structure from the compounds in the present invention.
Further, pyrazolo[1,5-a]pyridine derivatives are disclosed in WO2004/026872, WO2005/028445 and WO2005/077948. These compounds are, however, different in structure from the compound of the present invention or the compound of the present invention is not specifically disclosed in these literatures, as exemplified by the fact that WO2005/077948 describes only compounds wherein R3 is a methyl group but no compounds wherein R3 is a hydroxyl group or an amino group. Furthermore, the target enzymes of these compounds are also different from those of the compound of the present invention.